| Sonodynamic therapy is a new treatment for cancer based on photodynamic therapy, which has been widely researched by medical researchers because the depth of ultrasonic penetrating ability overcame the limitations of the light. But how to increase the stability of sonosensitizers and its amount in tumor, as well as further improve the effect of sonodynamic therapy still is a challenge for researchers.Liposome as the most commonly nano carrier could effectively increase the stability of drug, and improve the effect of sonodynamic therapy with the increased accumulation of tumor site through enhanced permeability and retention effect. In addition, the membrane permeability of liposome could be controlled by sonosensitizers. In the presence of ultrasound, reactive oxygen species produced by activated sonosensitizers oxidative liposome through reacting with unsaturated acid of phospholipids, which lead liposome membrane permeability increased and the drug released. However, in the absent of ultrasound the stability of liposome could be improved by sonosensitizers. In this paper, a drug delivery system with ultrasonic controlled function was used as the carrier of sodium diethyldithiocarbamate(superoxide enzyme inhibitor) for targeting sonodynamic therapy of tumor, which was prepared by introducing a higher production rate of active oxygen sonosensitizer(hematoporphyrin monomethyl ether) into liposome as a control switch.In the second chapter of this thesis, the ultrasound trigged liposome was prepared by reverse evaporation method and its properties were studied. According to the result of orthogonal, the maximum load of sodium diethyldithiocarbamate and hematoporphyrin monomethyl ether could be realized when the concentration of sodium diethyldithiocarbamate is 4.8 mg/mL, the proportion of phosphatidylcholine and cholesterol was 3:1, the proportion of organic phase/internal aqueous phase was 4:1, the incubation temperature was 30℃. Under the condition, the prepared liposome was uniform and the average particle size was about 100 nm. The result of spectral analysis showed that liposome effectively reduced the aggregation degree of hematoporphyrin monomethyl ether and improved the stability of the drug,while maintaining the characteristics of the high yield of singlet oxygen. Under the environment of ultrasonic, acoustic controlled liposome showed high levels of ultrasonic sensitivity.In the third chapter of this thesis, the preparation of liposome in intracellular targeting, and its dark toxicity to cells and the synergistic antitumor activity was studied on MCF-7 breast cancer cells. The obvious nuclear targeting ability of ultrasound trigged liposome was observed through the fluorescent of hematoporphyrin monomethyl ether at 4 h after the treatment, Cytotoxicity results show that compared with free hematoporphyrin monomethyl ether liposome improved the light stability of hematoporphyrin monomethyl ether and reduced its dark toxicity, while the cells killing of hematoporphyrin monomethyl ether was enhanced under ultrasound. Then with sodium diethyldithiocarbamate added, the increased production of reactive oxygen species and enhanced cytotoxicity proved the synergy of sodium diethyldithiocarbamate in the treatment of sonodynamic therapy.The fourth chapter of this thesis, further research in the body of targeting and synergistic antitumor effect was carried out on tumor-burdened ICR mice. After tail vein injection, Ultrasonic controlled liposome showed good tumor targeting ability,and stranded for a long time within the tumor. The results of treatment showed that simple ultrasound was not able to inhibit tumor growth, and liposomal hematoporphyrin monomethyl ether inhibitory rate higher than that of free hematoporphyrin monomethyl ether, while joint sodium diethyldithiocarbamate showed stronger inhibitory tumor effect, fully prove that there were synergies in sonodynamic therapy. |
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